Known techniques of setting a calcium phosphate compound include the following.
For example, it has been previously reported that a set material is obtained by mixing a mixture of tetracalcium phosphate (hereinafter referred to as “TTCP”) and α-tricalcium phosphate (hereinafter referred to as “α-TCP”) with a liquid agent (Patent Literature 1). The first prior art already published states that a set material having a three-dimensional shape is obtained by using a raw material powder containing TTCP and/or α-TCP and having a Ca/P ratio (molar ratio of calcium to phosphorus) of 1.40 to 2.0, including a first step of forming a layer composed of the raw material powder and a second step of bringing a reactive solution that chemically reacts with the raw material powder into contact with at least a part of the layer to set the raw material powder, and repeating the first step and the second step to thereby build up a plurality of the layers (claim 1 of Patent Literature 1).
However, the structural formula of TTCP is Ca4(PO4)2O, and the Ca/P ratio of TTCP is 2.00. Further, the structural formula of α-TCP is Ca3(PO4)2, and the Ca/P ratio of α-TCP is 1.50.
Therefore, when only TTCP and α-TCP are mixed at any ratio, the Ca/P ratio of the mixture does not have a value of less than 1.50.
However, all the lower limits of the Ca/P ratio disclosed in the first prior art are 1.40, and there is no description in which the lower limit is 1.50.
The case where the lower limit of the Ca/P ratio of the mixture is less than 1.50 is limited to a case where a component other than TTCP and α-TCP is contained. Therefore, it is unknown from the first prior art what kind of result is obtained when a raw material consisting of TTCP and α-TCP (hereinafter referred to as a “biphasic SSCP powder portion”) is used.
Further, there is also description that a mixture can be used as a liquid agent to be used in the first prior art, the mixture being obtained by adding, to water, an organic acid such as citric acid, an organic acid salt such as sodium salt and potassium salt of the organic acid, an inorganic acid such as phosphoric acid, an inorganic acid salt such as sodium phosphate, sodium carbonate, potassium phosphate, and potassium carbonate, a pH adjuster, a thickener, an X-ray contrast medium, an antibacterial agent, a monosaccharide such as glucose and fructose, a disaccharide such as saccharose and maltose, a polysaccharide such as cellulose, chitin, and chitosan, a bone morphogenetic protein such as BMP, various preparations such as prostaglandin, and the like (Patent Literature 1, paragraph [0077]).
However, in the first prior art, there is no description about the setting time when the mixture and the liquid agent are mixed.
On the other hand, as a second prior art, there is proposed a method of producing TTCP including producing a raw material slurry by synthesizing a raw material component containing a calcium-supplying raw material and a phosphorus-supplying raw material by a wet process, then drying the raw material slurry, baking the dried raw material at 400 to 1200° C., and firing the baked raw material at 1300 to 1500° C. (Patent Literature 2).
The second prior art describes that monophasic TTCP is obtained.
Further, the second prior art describes calcium phosphate cement (CPC) obtained by mixing the resulting monophasic TTCP and dicalcium phosphate anhydrous (DCPA) at a molar ratio of 1:1.
The second prior art also describes that a set material is obtained by mixing the CPC with water.
Further, as a third prior art, there is also described a method of kneading a paste of TTCP and a paste of DCPA to set the pastes (Non Patent Literature 1).
As a fourth prior art, there is described a method of separately preparing a TTCP powder, an α-TCP powder, and a β-TCP powder and kneading each of the powder with a saturated aqueous solution of dicalcium phosphate dihydrate (hereinafter referred to as “DCPD”) to set the kneaded mixture (Non Patent Literature 2).
As a fifth prior art, there is described a method of kneading a TTCP powder and a saturated MCPM phosphoric acid solution to set the kneaded mixture (Non Patent Literature 3).
However, in the first to the fifth prior arts, when a biphasic SSCP powder portion is used, it is unknown how much the setting time of the kneaded material containing the biphasic SSCP powder portion will be.
Next, a prior art which has disclosed a TTCP/α-TCP solid solution will be described.
A sixth prior art discloses that a cement powder is obtained by mechanically mixing calcium carbonate (hereinafter referred to as “CaCO3”) and DCPD at a molar ratio of 5:6, heating the mixture for 5 hours at 1500° C., and grinding the resulting fired block.
Further, it is also disclosed that a set material is obtained by kneading the cement powder and a liquid agent (Non Patent Literature 4).
Furthermore, a seventh prior art also discloses that the ratio of Ca to P contained in a fired block can be adjusted in a range of 1.5 to 2.0 using CaCO3 and DCPD (Non Patent Literature 5).
The liquid agent used in the sixth prior art is either (1) 1 M orthophosphoric acid aqueous solution (powder-liquid ratio: 1.5), (2) 1 M sodium dihydrogenphosphate aqueous solution (powder-liquid ratio: 1.5), (3) 1 M sodium dihydrogenphosphate aqueous solution (powder-liquid ratio: 2.0), (4) 2 M sodium dihydrogenphosphate aqueous solution (powder-liquid ratio 1.5), (5) 2 M sodium dihydrogenphosphate aqueous solution (powder-liquid ratio: 2.0), (6) 1 M citric acid aqueous solution (powder-liquid ratio: 2.0), (7) 1 M citric acid aqueous solution (powder-liquid ratio: 2.5), or (8) 2 M citric acid aqueous solution (powder-liquid ratio: 1.5).
Further, the liquid agent used in the seventh prior art is 1 M sodium dihydrogenphosphate aqueous solution, and 0.6 ml of the liquid agent is used relative to 1.0 g of a powder portion containing 95 weights of TTCP/α-TCP solid solution and 5 weight % of apatite.
The sixth prior art also describes the setting time of the above kneaded material.
Specifically, it is described that, by kneading the cement powder and a liquid agent, the setting time of a kneaded material will be about 2 minutes when the liquid agent (8) is used, and the setting time of a kneaded material will be about 52 minutes when the liquid agent (2) is used.
However, it is described that, even when any of the above (1) to (8) is selected as a liquid agent, diffraction peaks derived from raw materials are detected for 72 hours from the start of kneading.
Further, the seventh prior art describes that, even after a lapse of 28 days, diffraction peaks derived from raw materials are detected in the resulting set material.
Thus, the sixth and seventh prior arts describe that, when a TTCP/α-TCP solid solution is used, a long period of time is required until setting reaction is completed.
Further, an eighth prior art discloses that a set material is obtained by mixing (A) a powder portion obtained by mixing nonstoichiometric TTCP with 2 M trisodium citrate aqueous solution at a powder-liquid ratio of 2.5 and (B) a liquid agent obtained by saturating 1.05 mol/L phosphoric acid aqueous solution having a pH of 2.1 with monocalcium phosphate monohydrate (hereinafter referred to as “MCPM”) (Non Patent Literature 6).
However, the eighth prior art does not specifically disclose the nonstoichiometric TTCP other than it has a Ca/P ratio of 1.81. Therefore, it is unknown from the eighth prior art how the nonstoichiometric TTCP has been obtained.
Further, the eighth prior art does not describe the information about how much the setting time is when the nonstoichiometric TTCP is mixed with the saturated MCPM phosphoric acid aqueous solution.
On the other hand, a ninth prior art describes that a set material is obtained by kneading a first paste and a second paste (Patent Literature 3).
Here, the first paste contains at least one of dicalcium phosphate anhydrous (hereinafter referred to as “DCPA”) and DCPD, and water, and the second paste is a nonaqueous paste containing TTCP.
The ninth prior art, which describes work time and setting time, also discloses that the setting time of a set material obtained by kneading the first paste and the second paste can be adjusted between 3 minutes and 26 minutes, and the work time can be adjusted between 1.3 minutes and 10 minutes.
However, in the case of the ninth prior art, single TTCP and at least one of DCPA and DCPD are used, and the information about the case where a biphasic SSCP powder portion is used is not disclosed.
Therefore, it is unknown that, when the biphasic SSCP powder portion is used, how much the work time and setting time will be.
Further, the ninth prior art also discloses that the set material obtained by kneading the first paste and the second paste can be used for bone grafting.
By the way, it is required that a bone graft material used for the purpose of grafting into bone defects be not only compatible and safe in that the material does not harm a body in which it is grafted but also not susceptible to infection by a disease germ, a virus, and the like. Further, it is required that the bone graft material have such physical and chemical stabilities that, after being grafted into bone defects, the bone graft material is difficult to outflow, dissolve, or move from the bone defects.
However, it is not necessarily sufficient that the bone graft material has compatibility, safety, non-susceptibility to infection, physical stability, and chemical stability described above. In addition to these properties, shape formability and shape maintainability are also required.
The shape formability refers to properties in which a material can be formed into an ideal shape to bone defects, and the shape maintainability refers to properties in which a material has physical properties that can endure a physical load required during grafting, and a set material thereof can maintain the shape for a certain period of time required until the bone is regenerated.
Furthermore, a bone graft material is also required to have bone replaceability in which the material itself is replaced by bone with the lapse of time in the body.
However, if calcium phosphate compounds other than hydroxyapatite (hereinafter referred to as “HA”), for example, unreacted TTCP and α-TCP, remain in the set material described in the first to the ninth prior arts described above, there will be a problem that the unreacted TTCP and α-TCP each chemically dissolve in the body fluid in the body.
This is because HA is supersaturated in the body fluid in the body, while all the calcium phosphate compounds are undersaturated in the body fluid in the body except that octacalcium phosphate (hereinafter referred to as “OCP”) is saturated in the body fluid in the body, and therefore, the calcium phosphate compounds other than HA dissolve in the body fluid in the body except OCP.
There is also a fundamental problem that, in the process of bone replacement, when calcium ions and phosphate ions which are ionized by dissolution are combined, partial bone formation occurs in a part that has reprecipitated as a minute crystal of HA which is the calcium phosphate compound that is the most stable in the body, and α-TCP or TTCP itself does not directly undergo bone replacement.
An ideal bone graft material has properties called osteoconductivity in which, when the graft material is grafted in the body, it is directly bonded to existing bone without the intervention of connective tissue.
However, although high-temperature HA obtained by firing, which is typified by the set material described in the first prior art, has osteoconductivity, it is not replaced by bone itself in the body, but it only compensates for the bone defects for a certain period of time as a space-making material with which the space is simply filled.
Therefore, in the process of bone regeneration progressing with time, the bond of the high-temperature HA to surrounding bone is gradually lost, and it has a risk of outflowing from a body as foreign matter someday.
Further, in the case of a set material in which unreacted TTCP and α-TCP remain, a loss by the dissolution in the body fluid occurs. Therefore, a hole or a gap is inevitably produced in the set material, and even if a new bone is formed in a part of the set material as a result, anticipation of the final shape is difficult.